Tuberculosis kills over 1.5 million people each year and the emergence of multiple and extensively drug resistant strains demands new approaches for the diagnosis, prevention, and cure of TB. Numerous aspects of mycobacterial physiology remain poorly understood, and the study of bacteriophages and the interactions between the mycobacteria and their phages presents uncommon opportunities to understand the mycobacteria. One unanticipated finding is that many of the mycobacteriophages are temperate, and form stable lysogens in which the phage DNA is stably integrated into the mycobacterial chromosome as a prophage. Far from being inert, these prophages express genes that play key roles role in providing defense from attack by other unrelated bacteriophages. The variety of systems is considerable, and although some are canonical mechanisms, such as restriction-modification (R-M) and membrane- mediated exclusion, most are conferred by genes of unknown function and lack bioinformatic motifs indicative of extant viral defense systems. Nonetheless, there is evidence that some of these systems function by interrupting normal mycobacterial growth, leading to growth arrest in a persistent-like state that deprives the phage of a home for productive replication. In addition to providing insights into mycobacterial physiology, viral defense systems can be powerful biotechnological drivers, with CRISPR-Cas and R-M systems being powerful examples. A newly identified prophage-encoded viral defense system is encoded by phage Sbash, which reduces infection by the unrelated phage Crossroads ? but not other phages ? by more than five orders of magnitude. Two Sbash genes are responsible for the defense, but their functions are unknown and it is not known how they confer defense or how they target Crossroads. Unusually, Crossroads escape from defense occurs by both heritable and non-heritable mechanisms. Understanding the mechanism of defense and the basis of the specificity will reveal insights into mycobacterial physiology and has the potential for biotechnological development.